dc.contributor |
Háskóli Íslands |
dc.contributor |
University of Iceland |
dc.contributor.author |
Louphrasitthiphol, Pakavarin |
dc.contributor.author |
Siddaway, Robert |
dc.contributor.author |
Loffreda, Alessia |
dc.contributor.author |
Pogenberg, Vivian |
dc.contributor.author |
Friedrichsen, Hans |
dc.contributor.author |
Schepsky, Alexander |
dc.contributor.author |
Zeng, Zhiqiang |
dc.contributor.author |
Lu, Min |
dc.contributor.author |
Strub, Thomas |
dc.contributor.author |
Freter, Rasmus |
dc.contributor.author |
Lisle, Richard |
dc.contributor.author |
Suer, Eda |
dc.contributor.author |
Thomas, Benjamin |
dc.contributor.author |
Schuster-Böckler, Benjamin |
dc.contributor.author |
Filippakopoulos, Panagis |
dc.contributor.author |
Middleton, Mark |
dc.contributor.author |
Lu, Xin |
dc.contributor.author |
Patton, E. Elizabeth |
dc.contributor.author |
Davidson, Irwin |
dc.contributor.author |
Lambert, Jean-Philippe |
dc.contributor.author |
Wilmanns, Matthias |
dc.contributor.author |
Steingrimsson, Eirikur |
dc.contributor.author |
Mazza, Davide |
dc.contributor.author |
Goding, Colin R. |
dc.date.accessioned |
2020-11-24T15:38:29Z |
dc.date.available |
2020-11-24T15:38:29Z |
dc.date.issued |
2020-08-06 |
dc.identifier.citation |
Louphrasitthiphol, P., Siddaway, R., Loffreda, A., Pogenberg, V., Friedrichsen, H., Schepsky, A., Zeng, Z., Lu, M., Strub, T., Freter, R., Lisle, R., Suer, E., Thomas, B., Schuster-Böckler, B., Filippakopoulos, P., Middleton, M., Lu, X., Patton, E.E., Davidson, I., Lambert, J.-P., Wilmanns, M., Steingrímsson, E., Mazza, D., Goding, C.R., 2020. Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution. Molecular Cell. doi:10.1016/j.molcel.2020.05.025 |
dc.identifier.issn |
1097-2765 |
dc.identifier.uri |
https://hdl.handle.net/20.500.11815/2240 |
dc.description |
Publisher's version (útgefin grein) |
dc.description.abstract |
It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability. |
dc.description.sponsorship |
The Piggybac vectors were provided by Kazuhiro Murakami (RIKEN, Kobe, Japan). This work was funded by the Ludwig Institute for Cancer Research (C.R.G., R.F., B.S.-B., E. Suer, and X.L. ), Cancer Research UK (CRUK) grant number C38302/A12981 , through a CRUK Oxford Centre Prize DPhil Studentship (HF), the Medical Research Council (R.S., Z.Z., P.F.; MR/N010051/1 and E.E.P.; MC_UU_00007/9 ), L’Oreal-Melanoma Research Alliance 401181 (E.E.P.), the Harry J. Lloyd Trust (R.S.), the Wellcome Trust (P.F. and A.S.), the Postdoc Fund of the University of Iceland (A.S.), the Oxford Biomedical Research Centre (R.L.), the Research Fund of Iceland (E.S.), a European Research Consolidator Award ( ZF-MEL-CHEMBIO 648489 ) (E.E.P.), the CNRS , INSERM , the Ligue Nationale Contre le Cancer , the Institut National du Cancer ( INCa ), the ANR-10-LABX-0030-INRT French state fund (I.D.), and a Junior 1 salary award from the Fonds de Recherche du Québec-Santé ( FRQ-S ). This work was also funded by operating grants from the Cancer Research Society (J.-P.L.), the Fondazione Cariplo (A.L. and D.M.; 2014-1157 ), and the Italian Cancer Research Association ( AIRC ; IG2018- 21897 ; D.M.). I.D. is an “équipe labellisée” of the Ligue Nationale Contre le Cancer . |
dc.format.extent |
472-487.e10 |
dc.language.iso |
en |
dc.publisher |
Elsevier BV |
dc.relation.ispartofseries |
Molecular Cell;79(3) |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Acetylation |
dc.subject |
bHLH-LZ |
dc.subject |
DNA-binding affinity |
dc.subject |
E-box |
dc.subject |
Melanocyte |
dc.subject |
Melanoma |
dc.subject |
MITF |
dc.subject |
Transcription factor |
dc.subject |
Sortuæxli |
dc.subject |
DNA-rannsóknir |
dc.title |
Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution |
dc.type |
info:eu-repo/semantics/article |
dcterms.license |
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
dc.description.version |
Peer Reviewed |
dc.identifier.journal |
Molecular Cell |
dc.identifier.doi |
10.1016/j.molcel.2020.05.025 |
dc.relation.url |
https://www.sciencedirect.com/science/article/pii/S1097276520303452?via%3Dihub |
dc.contributor.department |
Læknadeild (HÍ) |
dc.contributor.department |
Faculty of Medicine (UI) |
dc.contributor.school |
Heilbrigðisvísindasvið (HÍ) |
dc.contributor.school |
School of Health Sciences (UI) |